Transcription is a process by which genetic information encoded in DNA is transcribed into RNA. RNA polymerases I, II, and III are involved in the process of transcription. RNA polymerase I is localized in nucleosomes and is responsible for synthesis of the precursors of 28S, 5.8S, and 18S rRNAs. RNA polymerase II transcribes genes encoding proteins and produces small RNAs responsible for RNA splicing. RNA polymerase III functions in conjunction with the nucleolus and transcribes genes coding for tRNAs, 5S rRNA, and a series of small, stable RNAs.
Transcription of genes encoding proteins by RNA polymerase II is initiated on DNA sequences corresponding to the 5' cap of mRNAs. A highly conserved, 25-35 base pair DNA sequence, TATA box, is positioned upstream of the transcription start site in most eukaryotic genes. The function of the TATA box is to act as a promoter for transcription. RNA polymerase II and a series of transcription factors (TFIIA through TFIIH) form a transcription initiation complex which binds at the TATA box promoter region. The formation of this complex positions RNA polymerase II for the initiation of transcription.
The assembly of the transcription initiation complex begins with the binding of TFIID to the TATA box. The process continues by the association of the TFIIA-TFIID-TATA complex with the remaining transcription factors in the sequence of TFIIB, TFIIF-RNA polymerase II, TFIIE, TFIIH, and TFIIJ. Inhibitors or repressors that bind to the TFIID-promoter complex can potentially block further assembly of the transcription initiation complex. Binding of TFIIA to the TFIID-TATA complex prevents the binding of the inhibitors and allows the assembly to proceed.
Inhibition of transcription by repressor molecules is an important means for regulating transcription. Negative cofactor 2 (NC2) and Dr1-associated polypeptides (DRAP1 and Dr1) are two such repressors which regulate transcription in cells. NC2 consists of two subunits, termed NC2.alpha. and NC2.beta., and the latter is identical to Dr1 (Goppelt, A. et al. (1996) EMBO J. 15: 3105-3116) in primary sequence. NC2.alpha. and NC2.beta. possess a histone fold domain of the H2A-H2B type at the amino terminus and an acidic domain at the carboxy terminus. NC2.alpha. has a proline-rich domain and a second, internal acidic domain, and NC2.beta. has a basic domain and a Gln/Ala-rich domain. NC2 binds the TFIID-TATA promoter complex via the histone fold domains and directly inhibits the binding of TFIIB with the initiation complex. Repression of basal transcription requires the histone fold domains and both of the acidic carboxy-terminal domains of NC2 subunits. In nucleosomes, the histone fold effects dimerization and DNA-binding.
Similarly, DRAP1 and Dr1 form a heterodimer through the histone fold domains at the amino terminus of both peptides (Mermelstein, F. et al. (1996) Genes Dev. 10: 1033-1048). The heterodimer represses transcription by binding to the TFIID-TATA promoter complex. This precludes the association of TFIIA and/or TFIIB with the TFIID-TATA promoter complex and prematurely terminates the assembly of the transcription initiation complex.
The discovery of a new transcription repressor similar to NC2.alpha. and DRAP1 and the polynucleotides which encode it satisfies a need in the art by providing new compositions which are useful in diagnosing, preventing, and treating inflammation and disorders associated with cell proliferation and apoptosis.